DESCRIPTION (Investigator's Abstract): The objectives of this research proposal are to determine the mechanisms by which transplanted cholinergic nerve cells mediate their functional effects. They hypothesize that these grafted cells become functionally incorporated into the neural circuitry of the host brain and that their activity can be regulated by host-derived fiber inputs. They will test this hypothesis by determining high affinity choline uptake (HACU) in the hippocampal formation as a measure of the activity of cholinergic nerve cells and terminals. In normal animals hippocampal HACU is elevated as a result of spatial memory training. They anticipate that if grafted cholinergic neurons receive appropriate inputs from the host brain, then the activity of the transplanted cells should also increase during training and thus result in enhanced rates of graft-derived HACU. The second hypothesis is that transplantation of cholinergic neurons at multiple target sites will be more effective in ameliorating spatial memory deficits than transplanting at individual target sites alone. They will test this hypothesis by placing cholinergic cells into both the hippocampal formation and retrosplenial cortex. In normal animals both of these areas of brain receive cholinergic inputs from the region of the medial septal nucleus (MSN) and diagonal band of Broca (DBB). Furthermore, lesions of the hippocampus, retrosplenial cortex, or their afferent inputs result in spatial memory deficits. They expect, therefore, that animals with combined intra-hippocampal and intra-retrosplenial grafts of cholinergic MSN/DBB cells should exhibit enhanced spatial maze performances in comparison to animals with intra-hippocampal or intra-resplenial grafts alone. The third objective is to determine whether the behavioral effects mediated by transplanted cholinergic neurons are sustained when the grafted cells are subsequently removed. This question will be addressed by assessing the spatial memory performance of rats with intrahippocampal grafts of cholinergic neurons. After the stabilization of post-graft behavioral performance, the transplanted neurons will be selectively eliminated using the cholinergic neurotoxin AF64A. Behavioral performance will then be re-evaluated to determine whether the loss of the grafted neurons will affect various aspects of spatial memory function.